Generally, biocompatible polymers are used in performing various medical practices including diagnoses and treatments or in replacing body parts. Recently, studies have been actively performed on development of polymeric drug carriers having a regulated sol-gel transition by modifying a molecular structure of the constituent polymer to form a biodegradable polymer or an amphiphilic polymer having both a hydrophobic group and a hydrophilic group, or by forming a hydrogel using a block copolymer.
U.S. Pat. No. 5,476,909 discloses an A-B-A type triblock copolymer, wherein the hydrophobic block (A) is defiled as polylactide (PLA), polyglycolide (PGA), and copolymers thereof, and the hydrophilic block (B) is defined as polyethylene glycol (PEG) and derivatives thereof.
Additionally, U.S. Pat. No. 6,004,573 discloses an amphiphilic block copolymer useful as a drug carrier, which is a biodegradable and low molecular weight triblock copolymer comprising a hydrophobic block consisting of a polylactide (PLA)-polyglycolide (PGA) copolymer and a hydrophilic block consisting of polyethylene glycol (PEG). This triblock copolymer has an increased hydrophobic contents, and thus exists as a clear solution of sol at about from 5° C. to 25° C. and when administered into a human body, is spontaneously transformed into a gel, i.e., a water-containing semisolid at the body temperature (37° C.) with retaining the insoluble gel form in the body, and can slowly release the drug in the gel by a reverse thermal gelation.
However, the technologies described above have problems that the drug-loaded hydrogel, although sufficiently injected into a human body, can be detached from tissues due to its insufficient bioadhesiveness, or may undergo a biodegradation to cause an initial burst release phenomenon, thereby resulting in uncontrolled drug release over a long period of time.
Meanwhile, Korean Patent No. 665672 discloses a method of preparing a block copolymer hydrogel using poly(β-aminoester) as a pH-sensitive component. The temperature- and pH-sensitive block copolymer as prepared by the disclosed method is gelated at a pH ranging from 7.0 to 7.4, which is similar to that in the body and is isolated at a lower pH range, hence safely forming gel in the body without clogging an injection needle, shown by the conventional temperature-sensitive hydrogel on human injection. As such, the prepared block copolymer can be applied to a targeted drug delivery carrier capable of responding to a specific temperature and pH for from one week to two weeks.
However, the above-described hydrogel has problems that its main chain consists of an ester bond and an amide bond, both of which are biodegradable, thus rather sharply decreasing the gel strength at the early stage of human injection, and that it requires a complicated multi-step reaction to induce a urethane reaction with a starting material of polyurethane after reacting polyethylene glycol with the biodegradable polymers, and separation and purification of unreacted materials.
The present inventors, while working on the temperature- and pH-sensitive biocompatible polymers with a long-term sustained-release drug release profile, succeeded in synthesizing a hydrophilic and temperature-sensitive polyethylene glycol-poly(amino urethane urea) multi-block copolymer, and also confirmed that it has a long-term sustained-release drug release profile and the temperature- and pH-sensitive properties, and filed Korean Patent Application No. 10-2012-0071412 based on the same.
Under the circumstances, the present inventors, while endeavoring to find a method to further reduce the drug release rate of the temperature- and pH-sensitive multi-block copolymer, discovered that a conjugate of albumin and polyethylene glycol-poly(amino urethane) (PEG-PAL) or polyethylene glycol-poly(amino ester urethane) (PEG-PAEU) multiblock copolymer can significantly reduce the initial burst release of the drug, and also can further reduce the drug release rate to enable a long-term drug delivery, and completed the present invention.